Physicians' Academy for Cardiovascular Education

PCSK9 & lowering LDL cholesterol

Literature -

Proprotein convertase subtilisin/kexin type 9 (PCSK9):
From structure - function relation to therapeutic inhibition


Tibolla G, Norata GD, Artali R, Meneghetti F, Catapano AL.
Nutr Metab Cardiovasc Dis. 2011 Nov;21(11):835-43. Epub 2011 Sep 23.



Aims:

This short review aims at summarizing the current information on Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) structure and function focusing also on the therapeutic possibilities based on the inhibition of this protein.


Data synthesis:

PCSK9 has been recently discovered as the third gene involved in autosomal dominant hypercholesterolemia. PCSK9 binds and favors degradation of the low-density lipoprotein receptor (LDLR) and thereby modulates the plasma levels of LDL-cholesterol (LDL-C). Some of the natural occurring PCSK9 mutations increase the protein function (gain of function) and cause hypercholesterolemia, whereas loss of function mutations associate with hypocholesterolemia. Since the loss of a functional PCSK9 in humans is not associated with apparent deleterious effects, this protease is an attractive target for the development of lowering plasma LDL-C agents, either alone or in combination with statins.


Conclusion:

Inhibition of PCSK9 is emerging as a novel strategy for the treatment of hypercholesterolemia and data obtained from pre-clinical studies show that use of monoclonal antibodies, antisense oligonucleotides and short interfering RNA are effective in reducing LDL-C, clinical studies, accompanied by a better understanding of PCSK9 biology, are now necessary to address whether these new compounds will have a future in clinical practice.


Background

High plasma levels of LDL-cholesterol (LDL-C) largely determine the risk of cardiovascular disease. Plasma LDL-C is strongly correlated with the incidence of coronary heart disease (CHD).1
From clinical trials with lipid lowering drugs it became clear that cardiovascular risk is reduced when LDL-C levels are decreased.2 Plasma levels of LDL-C are highly variable, depending both on environmental and genetic factors.3 Individuals with autosomal dominant hypercholesterolemia (ADH) have elevated LDL-C levels and premature CHD, mostly caused by mutations in either the gene encoding the LDL-receptor (LDLR) or in the apoB-100 gene. A third mutation can be in the gene encoding PCSK9, which co-segregated with plasma LDL-C.4 Many mutations in the PCSK9 gene were associated with either hypocholesterolemia (loss of function) or hypercholesterolemia (gain of function); therefore this protein is an interesting target for treating dyslipidemias.



Therapeutic perspectives

Studies have shown that PCSK9 directly interacts with the LDLR within the cell and at the surface of the plasma membrane.5,6

Possible targets within the LDLR/PCSK9 pathway are (see figure):
  • Reduction of the PSCK9 mRNA
  • Inhibition of the LDLR/PCSK9 binding at the plasma membrane
  • Inhibition of the PSCK9 processing
  • Inhibition of the intracellular LDLR/PCSK9 binding
In developing effective therapies, the route of administration is very important. Oligonucleotides and monoclonal antibodies are not efficiently absorbed by the gastrointestinal tract; these molecules should be injected subcutaneously or intramuscularly.

Understanding of basic molecular mechanisms is important to predict the pharmacokinetic profile of various therapies.

Conclusion

PCSK9 is a promising target for influencing LDL-C metabolism and thereby cardiovascular risk.

For the development of effective PSCK9 inhibitors, a good understanding of its physiology and biology is necessary. Clinical trials with PSCK9 inhibitors in hypercholesterolemia have to elucidate their possible role in treating hypercholesterolemia.
PCSK9 targeting for the treatment of dyslipidemia

References

1. Third Report of the National Cholesterol Education Program (NCEP). Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 2002;106(25):3143e421.
2. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195e207.
3. Rao DC, Laskarzewski PM, Morrison JA, Khoury P, Kelly K, Wette R, et al. The Cincinnati lipid research clinic family study: cultural and biological determinants of lipids and lipoprotein concentrations. Am J Hum Genet 1982;34(6): 888e903.
4. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34(2):154e6.
5. Qian YW, Schmidt RJ, Zhang Y, Chu S, Lin A, Wang H, et al. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J Lipid Res 2007;48(7):1488e98.
6. Nassoury N, Blasiole DA, Tebon Oler A, Benjannet S, Hamelin J, Poupon V, et al. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic 2007;8(6):718e32.

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